tbuckley/cabot-search huggingface dataset:
A phase Ib study of anlotinib plus TQB2450 as a second-line investigational therapy in advanced hepatocellular carcinoma (aHCC).
Authors: Wen Zhang, Yongkun SUN, Huiying Zeng, Zheng Zhu, Meng Liang, Yue Han, Dong Yan, BO CHEN, Zhen Huang, Xinyu Bi, Hong Zhao, Ai-Ping Zhou
Journal: Journal of Clinical Oncology (2022)

e16184 Background: The combination of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitor (TKI) manifested high efficacy in front-line therapy for aHCC, which still deserves further exploration in second-line therapy. Anlotinib, an oral multi-targeted TKI that mainly blocks VEGF/VEGFR pathway, has been approved for several solid tumor types in china. Anlotinib plus TQB2450, a novel anti-PD-L1 mAb, might be a promising strategy. This study aimed to evaluate the efficacy and safety of this regimen as second-line treatment in aHCC patients (pts). Methods: Pts with aHCC, ≥18 years, Child Pugh class A-B (scores ≤ 8), ECOG PS of 0-1, BCLC stage B or C, ≥ 1 measurable lesion (per RECIST v1.1) and progressed/tolerated after first-line treatment were eligible. Pts received anlotinib (10-12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200mg, iv, d1, q3w). In the dose-escalation stage, anlotinib dose was explored from 10mg to 12mg. Dose expansion was performed after the determination of the maximum tolerable dose. Tumor assessment was evaluated according to the RECIST 1.1 per investigators, supplemented by iRECIST. The primary endpoints were ORR and safety. Secondary endpoints included PFS, DCR and OS. Results: 19 pts were enrolled between 16 May 2019 and 16 Jan 2020. The median age of pts was 52 years (range: 37-67), 89.5% pts were male, 94.7% pts were ECOG 0 and 78.9% had BCLC staging C. Both 10mg and 12mg were tolerable during the dose-escalation stage. At the cut off date (Jan 29, 2022), the median follow-up duration was 9.13 months. Of the 19 evaluable patients, 4 had PR, 8 had SD, 5 had PD, and 2 pts were NE. Confirmed ORR was 23.5% (95%CI: 6.8-49.9), DCR was 76.5% (95%CI: 50.1-93.2). The median PFS was 5.49 (3.46-7.51) months, and median DOR of 12.95 (5.26-20.63) months was achieved. Treatment-related adverse events (TRAEs) of any grade were recorded in 73.7% pts, ≥ grade 3 TRAEs were observed in 7 patients, with gastrointestinal reaction (15.8%), leucopenia (5.3%), neutropenia (5.3%), thrombocytopenia (5.3%), ALT increased (5.3%). Conclusions: Anlotinib plus TQB2450 was tolerable and showed preliminary antitumor activity in pre-treated aHCC. Further investigation in larger population is warranted. Clinical trial information: NCT03825705.
Family history assessment to identify patients at risk for hereditary cancer syndromes in community oncology practices.
Authors: Sarah Austin, Erika Hanson, Jennifer J. Griggs, Ken Resnicow, Elena Martinez Stoffel
Journal: Journal of Clinical Oncology (2022)

e18735 Background: Identification of hereditary cancer syndromes can have implications for cancer treatment and prevention. However, only a fraction of cancer patients undergo germline genetic testing (GT). We employed a family health history tool (FHHT) to assist in identifying cancer patients eligible for GT in the outpatient oncology setting. Methods: Patients with cancer with a visit scheduled at one of two community-based oncology practices received email invitations to complete a web-based FHHT that elicits cancer type and age at diagnosis for 1 st and 2 nd degree relatives. NCCN guidelines were applied to identify individuals meeting clinical criteria for GT. We compared proportions of individuals eligible for GT by sex and cancer type using Fisher’s exact tests. Results: Of the 1292 cancer patients seen over a 4-month period, 276 (21.4%) completed the FHHT. Of those, 58% were female (N = 160) and breast cancer was the most common cancer diagnosis (N = 73, 26.4%), followed by prostate (N = 25, 9.1%) and colorectal cancer (CRC) (N = 15, 5.4%). 59 (21.3%) patients met criteria for GT, including 49.3% of those with breast cancer (N = 36), 66.7% of those with CRC (N = 10), 28% of those with prostate (N = 7), and 100% of those with pancreatic and ovarian cancers (N = 3 each). Breast cancer accounted for 61% of those meeting GT criteria, including personal history of breast cancer age &lt; 50 (N = 17), and personal history of breast cancer with family history of ovarian cancer (N = 7). The proportion of CRC patients meeting GT criteria was higher than for breast cancer (66.7% vs 49.3%). Seven of 10 (70%) CRC patients meeting GT criteria would not have been identified without their accompanying family history. Overall, women were more likely than men to meet GT criteria (OR 1.8, 95% CI: 1.01 to 3.47, p = 0.045). Conclusions: Approximately 1 in 5 cancer patients who were invited to complete the FHHT met NCCN guidelines for GT. While a personal history of young breast cancer was the most common GT eligibility criterion, the proportion of patients eligible for GT was highest among CRC. Across all cancer types, family history increased the number of patient meeting GT criteria by 42.4%. Implementing a patient-facing family history tool can assist community oncologists in clinically appropriate identification of cancer patients who are eligible for GT. While 48% of patients who completed the FHHT met GT criteria, generalizability is limited due to small sample size.[Table: see text]
Real-world PARPi treatment patterns and outcomes among patients with metastatic breast cancer.
Authors: Shaheenah S. Dawood, Kaylen Brzozowski
Journal: Journal of Clinical Oncology (2022)

e13005 Background: PARP inhibitors (PARPi) improves PFS among patients (pts) with HER2-ve metastatic breast cancer (MBC) and a BRCA1/2 mutation compared to physician choice of chemotherapy. The objective of this retrospective analysis was to look at the prognostic outcome associated with the use of PARPi therapy among pts with MBC in the real world setting. Methods: We utilized a federated network of de-identified health data representing approximately 84 million pt lives available through the TriNetX Research Network. We identified 767 pts with MBC treated with a PARPi. Overall survival (OS) was computed using the Kaplan Meier product limit method. Propensity score matching was performed on all comparisons of OS. Matching variables included age groups, prior platinum therapy, prior genitourinary malignancies, and secondary metastasis location. Results: Mean age was 56.3yrs. 718 pts had HER2- disease and 49pts had HER2+ disease. Median OS was 55.0m and 44.4m among pts with HER2- and HER2+ disease respectively. Median OS among was 58.3m and 48.6m among patients with HR+/HER2- and TNBC respectively(p = 0.18). Among pts with HR+/HER2- disease, 50.2% received PARPi in combination with endocrine therapy and 43.5% received CDK4/6i. Median OS among pts who received CDK4/6i + endocrine therapy prior to a PARPi and those that never received a CDK4/6i was 55.1m and 36.9m, respectively(p = 0.01). Among pts with TNBC, median OS among those that received PARPi prior to chemotherapy compared to those who received PARPi after chemotherapy was 52.5m and 47.6m respectively (p = 0.97). 169 HER2- pts had brain metastases. Median OS among pts who had brain metastases was 36.9m among pts with HR+/HER2- disease and 22.5m among pts with TNBC(p = 0.01). Among pts with no brain metastases, median OS was 60.6m among pts with HR+/HER2- disease and 56.3m among pts with TNBC(p = 0.91). Median OS among pts who were rechallenged with a PARPi compared to those who were not rechallenged with a PARPi was 58.3m vs 42m respectively (p = 0.05). Conclusions: To our knowledge this is the first data set to report activity of CDK4/6i among pts with HR+/HER2- MBC who received a PARPi, with an observed 18m OS advantage compared to pts who did not receive a CDK4/6i. In absence of brain metastases OS of pts with TNBC and HR+/HER2- is similar when treated with a PARPi.
Adjusting the TMIST study design to accommodate slower than expected accrual: ECOG-ACRIN EA1151.
Authors: Etta Pisano, Constantine Gatsonis, Mitchell D. Schnall, Martin Yaffe, Melissa A. Troester, Ilana F. Gareen, Laura C. Collins, Amarinthia Curtis, Elodia B Cole, Jean Cormack, Jon Steingrimsson, Ruth C Carlos, Kathy Miller, Christopher Comstock
Journal: Journal of Clinical Oncology (2022)

TPS10614 Background: The ECOG-ACRIN Tomosynthesis Mammographic Imaging Screening Trial (TMIST), which opened in 2017, is a randomized trial designed to assess whether Tomosynthesis Mammography (TM) should replace Digital Mammography (DM) for breast cancer screening. It is hypothesized that women assigned to TM for 3-5 screening rounds will have fewer advanced breast cancers than the women assigned to DM. Advanced cancers are those that have distant metastases or positive nodes, are invasive tumors greater than or equal to 2.0 cm in size, or are invasive tumors greater than 1.0 cm in size that are triple negative or HER 2+. The initially planned enrollment of 164,946 women was due to be completed by the end of 2020, with follow-up concluded by 2025. There were substantial challenges in meeting this timeline, including the organizational and funding structure of the NCI National Clinical Trials Network which is dependent upon sites using their existing staffing resources (not always readily available at the time of study activation). This led to longer than anticipated start of enrollment for most interested sites and lower than anticipated annual enrollment per participating site based ultimately on the staffing support that could be allocated to manage TMIST. In addition, research staffing shortages and periodic research operations closures due to COVID-19 have also impacted enrolling TMIST sites, though unevenly, since the start of the pandemic. Enrollment plateaued at approximately 2,100 subjects per month by the end of 2020. With that accrual rate expected, the trial design was modified to reduce the sample size so that the study could be completed by 2027. Methods: With the approval of the NCI CIRB, we changed how the primary endpoint measure for TMIST is assessed from the number of advanced cancers that occur by 4.5 years after randomization to the time from randomization to occurrence of advanced cancers. All advanced cancers occurring within 7 years of randomization are now included and all participants followed for at least three years. In addition, the power of the study of the study was modified from 0.9 to 0.85, while the originally assumed effect size at 4.5 years was retained These changes allowed a reduction of sample size to 128,905, with subject recruitment projected to end in 2024. As of February 14, 2022, there are 125 sites open, 114 in the U.S. and 11 in other countries, with an additional 31 sites planning to open. As of February 14, 2022, a total of 63,845 women have been enrolled in the trial worldwide at 115 sites, with 20% of US participants self-identifying as belonging to minority racial and ethnic groups and 70% consenting to optional blood and/or buccal cell collection. Clinical trial information: NCT03233191.
A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation
Authors: Marijana Vujkovic, Shweta Ramdas, Kim M. Lorenz, Xiuqing Guo, Rebecca Darlay, Heather J. Cordell, Jing He, Yevgeniy Gindin, Chuhan Chung, Robert P. Myers, Carolin V. Schneider, Joseph Park, Kyung Min Lee, Marina Serper, Rotonya M. Carr, David E. Kaplan, Mary E. Haas, Matthew T. MacLean, Walter R. Witschey, Xiang Zhu, Catherine Tcheandjieu, Rachel L. Kember, Henry R. Kranzler, Anurag Verma, Ayush Giri, Derek M. Klarin, Yan V. Sun, Jie Huang, Jennifer E. Huffman, Kate Townsend Creasy, Nicholas J. Hand, Ching-Ti Liu, Michelle T. Long, Jie Yao, Matthew Budoff, Jingyi Tan, Xiaohui Li, Henry J. Lin, Yii-Der Ida Chen, Kent D. Taylor, Ruey-Kang Chang, Ronald M. Krauss, Silvia Vilarinho, Joseph Brancale, Jonas B. Nielsen, Adam E. Locke, Marcus B. Jones, Niek Verweij, Aris Baras, K. Rajender Reddy, Brent A. Neuschwander-Tetri, Jeffrey B. Schwimmer, Arun J. Sanyal, Naga Chalasani, Kathleen A. Ryan, Braxton D. Mitchell, Dipender Gill, Andrew D. Wells, Elisabetta Manduchi, Yedidya Saiman, Nadim Mahmud, Donald R. Miller, Peter D. Reaven, Lawrence S. Phillips, Sumitra Muralidhar, Scott L. DuVall, Jennifer S. Lee, Themistocles L. Assimes, Saiju Pyarajan, Kelly Cho, Todd L. Edwards, Scott M. Damrauer, Peter W. Wilson, J. Michael Gaziano, Christopher J. O’Donnell, Amit V. Khera, Struan F. A. Grant, Christopher D. Brown, Philip S. Tsao, Danish Saleheen, Luca A. Lotta, Lisa Bastarache, Quentin M. Anstee, Ann K. Daly, James B. Meigs, Jerome I. Rotter, Julie A. Lynch, Daniel J. Rader, Benjamin F. Voight, Kyong-Mi Chang
Journal: Nature Genetics (2022)
Predicting breast cancer in women using liquid biopsy-derived glycoproteomic markers.
Authors: Alan Mitchell, Apoorva Srinivasan, Gege Xu, Rachel Rice, Alyn Castellanos, Ranjan Bhadra, Danie Serie, Xin Cong, Klaus Lindpaintner
Journal: Journal of Clinical Oncology (2022)

e12545 Background: Breast cancer is the most common cancer among women worldwide.Traditional methods of cancer detection such as tissue biopsy are invasive, costly, time consuming and not amenable for repetition. As a result, minimally invasive liquid biopsies, especially blood-based biomarkers show potential value for breast cancer risk prediction and early detection. In this study, we investigated the use of serum glycoproteins circulating in blood to identify a panel of potential prognostic markers that may aid in predicting breast cancer in women. Methods: We applied a novel platform for characterizing blood glycoproteomic biomarkers, combining liquid-chromatography/mass spectrometry (LC-MS) with artificial intelligence/neural networks (AI-NN) to analyze serum samples from 279 breast cancer patients (median age 56 years, with stage 0-4 N’s: 1 / 83 / 114 / 56 / 25) and 102 healthy control samples (median age 52 years). A panel of 596 serum glycosylated and non-glycosylated peptides, representing 71 serum proteins, were analyzed. Age-adjusted differential expression analysis for 596 normalized biomarkers were performed to evaluate statistically significant differential abundances using an FDR q-value of 0.05 as a cutoff. Using the top differentially expressed markers as input, a LASSO penalized logistic regression model with 5-fold repeated cross validation was applied to identify the top biomarkers contributing to the separation between healthy controls and breast cancer patients. Results: We identified 243 out of 596 markers that were differentially expressed (FDR &lt;&lt;0.05) between breast cancer samples and healthy controls. Out of those, 11 markers were obtained as the top predictors in classifying breast cancer patients and healthy controls. The classification algorithm yielded an accuracy of 94% (95.9% sensitivity, 88.7% specificity) and an AUC of 0.983 on the training set. This classifier was validated on an independent test set with 30% of the subjects, yielding an accuracy of 93% (96.4% sensitivity, 83.9% specificity) and an AUC of 0.974. Test sensitivity was high across stages, at 96% / 90% / 95% / 90% in stages 1-4, respectively. Conclusions: Based on the results, we conclude that circulating glycoproteins in serum may be useful in screening applications in breast cancer, and strongly demonstrates the utility of glycoprotein profiles as a powerful non-invasive diagnostic tool.
Oncolytic and protective effects of strain 100 of a new group of non-classified rotavirus of reoviridae family on B16/F10 melanoma growth in experiment.
Authors: Elena P. Kolpakova, Elena Yu Zlatnik, Oksana G. Shulgina, Ekaterina I. Zolotareva, Larisa N. Vashchenko, Tatiana V. Ausheva, Svetlana M. Bakulina, Irina R. Dashkova
Journal: Journal of Clinical Oncology (2022)

e21587 Background: The purpose of this study was to assess the effect of a strain 100 of a new group of rotavirus of Reoviridae family on the growth of transplantable B16/F10 melanoma in mice and the survival of the animals. Methods: We studied the strain 100 of a new group of rotavirus of Reoviridae family (RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK 100 is a live attenuated non-pathogenic virus growing on pig embryo kidney cell culture with concentration 5·10 9 per 1 ml. The dynamics of melanoma growth and the survival of tumor-bearing animals receiving RVK were studied in 25 male mice divided into 5 equal groups, each n = 5. RVK was administered intramuscularly and orally once a week 0.3 mL and 25 µL, respectively: to groups 1-2 21 days prior to the tumor inoculation, a total of 4 injections (“vaccination” regimen); to groups 3-4 – 7 days after tumor inoculation with the onset of tumor nodes, a total of 3 injections (“treatment” regimen); group 5 included controls receiving 0.85% NaCl solution. Groups 1 and 3 received live RVK, groups 2 and 4 - RVK inactivated by UV radiation. Results: Survival of mice in groups 1-2 receiving both live and inactivated RVK in the “vaccination” regimen was increased statistically significantly: in group 1, Me = 25 days after melanoma transplantation (LQ 24; UQ 30), in group 2 Me = 26 days (LQ 25; UQ 30), in controls Me = 14 days (LQ 10; UQ 22); p = 0.032 and p = 0.0079, respectively. RVK administration in the “treatment” regimen did not cause such changes. While mice of group 3 receiving the live strain 100 showed a tendency to higher survival, compared to controls (Me = 23 days, LQ 22; UQ 24, p = 0.056), the administration of inactivated RVK (group 4) did not significantly improve the survival of animals, compared to controls (Me = 22 days (LQ 21; UQ 33, p = 0.151). Conclusions: Improved survival of animals with B16/F10 melanoma after the RVK administration indicates the virus ability to slow down tumor growth and confirms our previously published data on the RVK strain 228, although, in contrast to it, the strain 100 is able to increase the survival rate of tumor-bearing mice only when used in the “vaccination” regimen, which refers mainly to the inactivated virus. Since the inactivation of the RVK strain 100 eliminates its effect when used in the “treatment”, but not “vaccination” regimen, it seems to be associated with an immunostimulatory effect but not with an oncolytic one.
Racial and Ethnic Bias in Pulse Oximetry and Clinical Outcomes
Authors: Valeria S. M. Valbuena, Raina M. Merchant, Catherine L. Hough
Journal: JAMA Internal Medicine (2022)

Ashraf Fawzy, MD, MPH; Tianshi David Wu, MD, MHS; Kunbo Wang, MS; Matthew L. Robinson, MD; Jad Farha, MD; Amanda Bradke, MD, MA; Sherita H. Golden, MD, MHS; Yanxun Xu, PhD; Brian T. Garibaldi, MD, MEHP
Distinct skin microbiome community structures in congenital ichthyosis
Authors: Khek-Chian Tham, Rachel Lefferdink, Kaibo Duan, Seong Soo Lim, X.F. Colin C. Wong, Erin Ibler, Benedict Wu, Hajar Abu-Zayed, Stephanie M. Rangel, Ester Del Duca, Mashkura Chowdhury, Margot Chima, Hee Jee Kim, Bernett Lee, Emma Guttman-Yassky, Amy S. Paller, John E. A. Common
Journal: British Journal of Dermatology (2022)

The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored.To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes.Body site-matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis.Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes.The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic? The skin microbiome of congenital ichthyoses is largely unexplored. Microbes play an important role in pathogenesis, as infections are common. The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add? A common skin microbiome signature was observed across congenital ichthyoses. Distinct microbiome features were associated with ichthyosis subtypes. Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message? These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention.
MODL-18. Enhancing anti-CD47 mAb efficacy with radiotherapy for Group 3 paediatric medulloblastoma in preclinical models
Authors: Zahra Abbas, Jessica Buck, Mathew Ancliffe, Clara Andradas Arias, Meegan Howlett, Hilary Hii, Terrance Johns, Siddhartha Mitra, Nicholas Gottardo, Raelene Endersby
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is the most common paediatric brain cancer. Standard treatment approaches, including craniospinal irradiation (CSI), can result in severe lifelong side effects and have not changed for decades resulting in a stagnation of survival outcomes for children with aggressive medulloblastoma. Despite successes in other cancers, no immunotherapies have been approved for use in paediatric medulloblastoma. Unlike other solid tumours, medulloblastomas are myeloid dominant, and immunotherapies must be rationally designed with the tumour microenvironment in mind. Anti-CD47 antibody therapy activates macrophages against cancer cells by blocking anti-phagocytic signalling mediated by CD47-SIRPa ligation and has shown preclinical efficacy in brain cancer models. We have developed preclinical CSI protocols that mimic clinical treatment response using a small animal radiotherapy platform. We show that CSI depletes adaptive immune cells in the brain, increasing the proportional abundance of myeloid cells, suggesting an opportunity to combine radiation with myeloid-targeted immunotherapy. We show that anti-CD47 therapy is ineffective as a single agent against a patient-derived xenograft model of Group 3 medulloblastoma (SJ_MB002), and that while the CSI protocol causes temporary tumour regression, the combination of anti-CD47 with CSI results in marked and persistent tumour regression. To enhance our preclinical evaluation of CSI and anti-CD47, we have developed new mouse models that more accurately reflect the developing microenvironment of children and show that immune populations in paediatric brain are distinct from adult mouse brain. Future work will elucidate the mechanisms by which radiotherapy alters the medulloblastoma microenvironment to enhance the anti-tumour activity of myeloid immune cells in the brain. By evaluating this novel combination of immunotherapy with standard medulloblastoma treatments, in age-appropriate models, our research should facilitate the rational selection and rapid translation of optimised treatment combinations for future medulloblastoma clinical trials.